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Nikkilä R, Mäkitie A, Joensuu H, Markkanen S, Elenius K, Monni O, Palotie A, Saarentaus E, Salo T, Bizaki-Vallaskangas A. Novel Genetic Risk Variants Associated with Oral Tongue Squamous Cell Carcinoma. Head Neck Pathol 2025; 19:45. [PMID: 40278994 PMCID: PMC12031715 DOI: 10.1007/s12105-025-01784-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Accepted: 03/28/2025] [Indexed: 04/26/2025]
Abstract
PURPOSE Limited data from genome-wide association studies (GWAS) focusing on oral tongue squamous cell carcinoma (OTSCC) are available. The present study was conducted to explore genetic associations for OTSCC. METHODS A GWAS on 376 cases of OTSCC was conducted using the FinnGen Data Freeze-12 dataset. The case-cohort included 205 males and 171 females. Cases with malignancies involving the base of the tongue or lingual tonsil were excluded from the case-cohort. Individuals with no recorded history of malignancy were used as controls (n = 407,067). A Phenome-wide association study (PheWAS) was performed for the lead variants to assess their co-associations with other cancers. RESULTS GWAS analysis identified three genome-wide significant loci associated with OTSCC (p < 5 × 10-8), located at 5p15.33 (rs27067 near gene LINC01511), 10q24 (rs1007771191 near RPS3AP36), and 20p12.3 (rs1438070080 near PLCB1), respectively. PheWAS showed associations of rs27067 mainly with prostate cancer (OR = 1.06, p = 5.41 × 10-7), and seborrheic keratosis (OR = 1.11, p = 1.51 × 10-11). A co-directional effect with melanoma was also observed (OR = 0.93, p = 6.24 × 10-5). CONCLUSION The GWAS detected two novel genetic associations with OTSCC. Further research is needed to identify the genes at these loci that contribute to the molecular pathogenesis of OTSCC.
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Affiliation(s)
- Rayan Nikkilä
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer and Research, Helsinki, Finland
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Antti Mäkitie
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Heikki Joensuu
- Department of Oncology, HUS Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Saara Markkanen
- Department of Otolaryngology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- The Wellbeing Services County of Pirkanmaa, Tampere, Finland
| | - Klaus Elenius
- Institute of Biomedicine, and MediCity Research Laboratory, University of Turku, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Department of Oncology, Turku University Hospital, Turku, Finland
| | - Outi Monni
- Department of Oncology, HUS Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland
- Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Aarno Palotie
- Institute for Molecular Medicine Finland and the Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
- The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology, and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - Elmo Saarentaus
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
- Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Institute for Molecular Medicine Finland and the Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Tuula Salo
- Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
- Translational Immunology Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Pathology, HUS Helsinki University Hospital, Helsinki, Finland
- Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland
- Medical Research Center, Oulu University Hospital, Oulu, Finland
| | - Argyro Bizaki-Vallaskangas
- Department of Otolaryngology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- The Wellbeing Services County of Pirkanmaa, Tampere, Finland.
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Hosseiniyan Khatibi SM, Rahbar Saadat Y, Hejazian SM, Sharifi S, Ardalan M, Teshnehlab M, Zununi Vahed S, Pirmoradi S. Decoding the Possible Molecular Mechanisms in Pediatric Wilms Tumor and Rhabdoid Tumor of the Kidney through Machine Learning Approaches. Fetal Pediatr Pathol 2023; 42:825-844. [PMID: 37548233 DOI: 10.1080/15513815.2023.2242979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/26/2023] [Indexed: 08/08/2023]
Abstract
Objective: Wilms tumor (WT) and Rhabdoid tumor (RT) are pediatric renal tumors and their differentiation is based on histopathological and molecular analysis. The present study aimed to introduce the panels of mRNAs and microRNAs involved in the pathogenesis of these cancers using deep learning algorithms. Methods: Filter, graph, and association rule mining algorithms were applied to the mRNAs/microRNAs data. Results: Candidate miRNAs and mRNAs with high accuracy (AUC: 97%/93% and 94%/97%, respectively) could differentiate the WT and RT classes in training and test data. Let-7a-2 and C19orf24 were identified in the WT, while miR-199b and RP1-3E10.2 were detected in the RT by analysis of Association Rule Mining. Conclusion: The application of the machine learning methods could identify mRNA/miRNA patterns to discriminate WT from RT. The identified miRNAs/mRNAs panels could offer novel insights into the underlying molecular mechanisms that are responsible for the initiation and development of these cancers. They may provide further insight into the pathogenesis, prognosis, diagnosis, and molecular-targeted therapy in pediatric renal tumors.
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Affiliation(s)
- Seyed Mahdi Hosseiniyan Khatibi
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Simin Sharifi
- Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz Iran
| | | | - Mohammad Teshnehlab
- Department of Electrical and Computer Engineering, K.N. Toosi University of Technology, Tehran, Iran
| | | | - Saeed Pirmoradi
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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Liu L, Liang L, Yang C, Chen Y. Machine learning-based solution reveals cuproptosis features in inflammatory bowel disease. Front Immunol 2023; 14:1136991. [PMID: 37275904 PMCID: PMC10233155 DOI: 10.3389/fimmu.2023.1136991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 03/23/2023] [Indexed: 06/07/2023] Open
Abstract
BACKGROUND Cuproptosis, a new cell death mode, is majorly modulated by mitochondrial metabolism and protein lipoylation. Nonetheless, cuproptosis-related genes (CRGs) have not yet been thoroughly studied for their clinical significance and relationship with the immune microenvironment in inflammatory bowel disease (IBD). METHODS We screened CRGs that had a significant correlation with immune status, which was determined utilizing single-sample GSEA (ssGSEA) and Gene Expression Omnibus datasets (GSE75214). Furthermore, utilizing the R package "CensusClusterPlus", these CRGs' expression was used to obtain different patient clusters. Subsequently, gene-set enrichment analysis (GSEA), gene set variation analysis (GSVA), and CIBERSORT assessed the variations in the enrichment of gene function and the abundance of immune cell infiltration and immune functions across these clusters. Additionally, weighted gene co-expression network analysis (WGCNA) and analysis of differentially expressed genes (DEGs) were executed, and for the purpose of identifying hub genes between these clusters, the construction of protein-protein interaction (PPI) network was done. Lastly, we used the GSE36807 and GSE10616 datasets as external validation cohorts to validate the immune profiles linked to the expression of CRG. ScRNA-seq profiling was then carried out using the publicly available dataset to examine the CRGs expression in various cell clusters and under various conditions. RESULTS Three CRGs, PDHA1, DLD, and FDX1, had a significant association with different immune profiles in IBD. Patients were subsequently classified into two clusters: low expression levels of DLD and PDHA1, and high expression levels of FDX1 were observed in Cluster 1 compared to Cluster 2. According to GSEA, Cluster 2 had a close association with the RNA processes and protein synthesis whereas Cluster 1 was substantially linked to environmental stress response and metabolism regulations. Furthermore, Cluster 2 had more immune cell types, which were characterized by abundant memory B cells, CD4+ T memory activated cells, and follicular helper T cells, and higher levels of immune-related molecules (CD44, CD276,CTLA4 and ICOS) than Cluster 1. During the analysis, the PPI network was divided into three significant MCODEs using the Molecular Complex Detection (MCODE) algorithm. The three MCODEs containing four genes respectively were linked to mitochondrial metabolism, cell development, ion and amino acid transport. Finally, external validation cohorts validated these findings, and scRNA-seq profiling demonstrated diverse intestinal cellular compositions with a wide variation in CRGs expression in the gut of IBD patients. CONCLUSIONS Cuproptosis has been implicated in IBD, with PDHA1, DLD, and FDX1 having the potential as immune biomarkers and therapeutic targets. These results offer a better understanding of the development of precise, dependable, and cutting-edge diagnosis and treatment of IBD.
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Affiliation(s)
- Le Liu
- Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Liping Liang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chenghai Yang
- Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Ye Chen
- Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Serrano-López EM, Coronado-Parra T, Marín-Vicente C, Szallasi Z, Gómez-Abellán V, López-Andreo MJ, Gragera M, Gómez-Fernández JC, López-Nicolás R, Corbalán-García S. Deciphering the Role and Signaling Pathways of PKCα in Luminal A Breast Cancer Cells. Int J Mol Sci 2022; 23:ijms232214023. [PMID: 36430510 PMCID: PMC9696894 DOI: 10.3390/ijms232214023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/11/2022] [Accepted: 10/26/2022] [Indexed: 11/16/2022] Open
Abstract
Protein kinase C (PKC) comprises a family of highly related serine/threonine protein kinases involved in multiple signaling pathways, which control cell proliferation, survival, and differentiation. The role of PKCα in cancer has been studied for many years. However, it has been impossible to establish whether PKCα acts as an oncogene or a tumor suppressor. Here, we analyzed the importance of PKCα in cellular processes such as proliferation, migration, or apoptosis by inhibiting its gene expression in a luminal A breast cancer cell line (MCF-7). Differential expression analysis and phospho-kinase arrays of PKCα-KD vs. PKCα-WT MCF-7 cells identified an essential set of proteins and oncogenic kinases of the JAK/STAT and PI3K/AKT pathways that were down-regulated, whereas IGF1R, ERK1/2, and p53 were up-regulated. In addition, unexpected genes related to the interferon pathway appeared down-regulated, while PLC, ERBB4, or PDGFA displayed up-regulated. The integration of this information clearly showed us the usefulness of inhibiting a multifunctional kinase-like PKCα in the first step to control the tumor phenotype. Then allowing us to design a possible selection of specific inhibitors for the unexpected up-regulated pathways to further provide a second step of treatment to inhibit the proliferation and migration of MCF-7 cells. The results of this study suggest that PKCα plays an oncogenic role in this type of breast cancer model. In addition, it reveals the signaling mode of PKCα at both gene expression and kinase activation. In this way, a wide range of proteins can implement a new strategy to fine-tune the control of crucial functions in these cells and pave the way for designing targeted cancer therapies.
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Affiliation(s)
- Emilio M. Serrano-López
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, El Palmar, 30120 Murcia, Spain
| | - Teresa Coronado-Parra
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Microscopy Core Unit, Área Científica y Técnica de Investigación, Universidad de Murcia, 30100 Murcia, Spain
| | - Consuelo Marín-Vicente
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Cardiovascular Proteomics and Developmental Biology Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
| | - Zoltan Szallasi
- Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Bioinformatics, Semmelweis University, H-1092 Budapest, Hungary
| | - Victoria Gómez-Abellán
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Department of Cellular Biology and Histology, Biology School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
| | - María José López-Andreo
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Molecular Biology Unit, Área Científica y Técnica de Investigación, Universidad de Murcia, 30100 Murcia, Spain
| | - Marcos Gragera
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Centro Nacional Biotecnología, Consejo Superior de Investigaciones Científicas, 28006 Madrid, Spain
| | - Juan C. Gómez-Fernández
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, El Palmar, 30120 Murcia, Spain
| | - Rubén López-Nicolás
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, El Palmar, 30120 Murcia, Spain
- Department of Bromatology and Nutrition, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Correspondence: (R.L.-N.); (S.C.-G.)
| | - Senena Corbalán-García
- Department of Biochemistry and Molecular Biology A, Veterinary School, Universidad de Murcia, CEIR Campus Mare Nostrum (CMN), 30100 Murcia, Spain
- Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, El Palmar, 30120 Murcia, Spain
- Correspondence: (R.L.-N.); (S.C.-G.)
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Jiang HZ, Yang B, Jiang YL, Liu X, Chen DL, Long FX, Yang Z, Tang DX. Development and validation of prognostic models for colon adenocarcinoma based on combined immune-and metabolism-related genes. Front Oncol 2022; 12:1025397. [PMID: 36387195 PMCID: PMC9661394 DOI: 10.3389/fonc.2022.1025397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 09/30/2022] [Indexed: 11/02/2023] Open
Abstract
BACKGROUND The heterogeneity of tumor tissue is one of the reasons for the poor effect of tumor treatment, which is mainly affected by the tumor immune microenvironment and metabolic reprogramming. But more research is needed to find out how the tumor microenvironment (TME) and metabolic features of colon adenocarcinoma (COAD) are related. METHODS We obtained the transcriptomic and clinical data information of COAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering analysis was used to identify different molecular subtypes, identify differentially expressed genes (DEGs) associated with immune-and metabolism-related genes (IMRGs) prognosis. Univariate and multivariable Cox regression analysis and Lasso regression analysis were applied to construct the prognostic models based on the IMRG risk score. The correlations between risk scores and TME, immune cell infiltration, and immune checkpoint genes were investigated. Lastly, potential appropriate drugs related to the risk score were screened by drug sensitivity analysis. RESULTS By consensus clustering analysis, we identified two distinct molecular subtypes. It was also found that the multilayered IMRG subtypes were associated with the patient's clinicopathological characteristics, prognosis, and TME cell infiltration characteristics. Meanwhile, a prognostic model based on the risk score of IMRGs was constructed and its predictive power was verified internally and externally. Clinicopathological analysis and nomogram give it better clinical guidance. The IMRG risk score plays a key role in immune microenvironment infiltration. Patients in the high-risk groups of microsatellite instability (MSI) and tumor mutational burden (TMB) were found to, although with poor prognosis, actively respond to immunotherapy. Furthermore, IMRG risk scores were significantly associated with immune checkpoint gene expression. The potential drug sensitivity study helps come up with and choose a chemotherapy treatment plan. CONCLUSION Our comprehensive analysis of IMRG signatures revealed a broad range of regulatory mechanisms affecting the tumor immune microenvironment (TIME), immune landscape, clinicopathological features, and prognosis. And to explore the potential drugs for immunotherapy. It will help to better understand the molecular mechanisms of COAD and provide new directions for disease treatment.
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Affiliation(s)
- Hui-zhong Jiang
- College of Graduate, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Bing Yang
- College of Graduate, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Ya-li Jiang
- College of Graduate, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Xun Liu
- College of Graduate, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Da-lin Chen
- College of Graduate, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Feng-xi Long
- College of Graduate, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Zhu Yang
- College of Graduate, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Dong-xin Tang
- College of Graduate, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
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Liu X, Hu J, Liu B. Characteristics and clinical significance of lipid metabolism in patients with gastrointestinal stromal tumor. Lipids Health Dis 2022; 21:1. [PMID: 34991597 PMCID: PMC8740318 DOI: 10.1186/s12944-021-01613-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/13/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND To investigate the characteristics and clinical significance of serum lipids in patients with gastrointestinal stromal tumors (GISTs). METHODS The clinical and pathological data of 694 GIST patients in Liyuan hospital and Union hospital from 2012 to 2016 were retrospectively analyzed. Blood lipid levels in patients with varying degrees of risk were compared. RESULTS The findings showed that LDL-C, HDL-C, and CHOL increased significantly in women, and CD34 positive. In patients with tumors size less than 5 cm in diameter, TG, HDL-C, and CHOL were significantly higher. TG levels were significantly higher in DOG-1 (a marker and has a high specificity and sensitivity in the diagnosis of GIST) positive patients than in DOG-1 negative patients (P < 0.05). S-100 positive patients had lower HDL-C levels than S-100 negative patients (P < 0.05). Lipids indexes were found to be correlated with GIST risk stratification and tumor site (P < 0.05). TG/HDL-C was were significantly different among patients with GIST in different locations (P < 0.05). CONCLUSION The clinical and pathological characteristics of the patients with GIST are closely related to the level of blood lipids. To a certain extent, information about level of blood lipids can be helpful for distinguishing benign and malignant GIST.
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Affiliation(s)
- Xiaoling Liu
- Department of Endocrinology, Liyuan Hospital, Tongji Medical College, Huazhong University of Since and Technology, 39Yanhu Avenue, Hongshan District, Wuhan, 430022, Hubei, China
| | - Jun Hu
- Department of Endocrinology, Liyuan Hospital, Tongji Medical College, Huazhong University of Since and Technology, 39Yanhu Avenue, Hongshan District, Wuhan, 430022, Hubei, China.
| | - Bende Liu
- Department of Union Jiangnan Hospital Huazhong University of Science and Technology, 1 Wenhua Avenue, Jiangxia District, Wuhan, 430022, Hubei, China.
- Department of Cardiovascular system Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Jianghan District, Wuhan, 430022, Hubei, China.
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Gao X, Liu Q, Chen X, Chen S, Yang J, Liu Q, Cheng Y. Screening of tumor grade-related mRNAs and lncRNAs for Esophagus Squamous Cell Carcinoma. J Clin Lab Anal 2021; 35:e23797. [PMID: 33960436 PMCID: PMC8183932 DOI: 10.1002/jcla.23797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 11/25/2022] Open
Abstract
Background The goal of our study was to screen tumor grade‐related lncRNAs and mRNAs to reveal the underlying molecular mechanism of esophagus squamous cell carcinoma (ESCC). Methods The lncRNA and mRNA sequencing data were obtained from The Cancer Genome Atlas (TCGA). Tumor grade correlation analysis of lncRNAs and mRNAs was executed, followed by the functional enrichment analysis of all tumor grade‐related mRNAs. The differentially expression mRNAs (DEmRNAs) and differentially expressed lncRNAs (DElncRNAs) were obtained. PPI network and DEmRNA‐DElncRNA interaction analysis were constructed. The functional annotation of the DEmRNAs co‐expressed with DElncRNAs was performed. The expression levels of the candidate genes were validated using qRT‐PCR. Results A total of 1864 tumor grade‐related mRNAs (846 positively related and 1018 negatively related) and 552 tumor grade‐related lncRNAs (331 positively related and 221 negatively related) were obtained. The top 10 significantly grade‐related mRNAs and lncRNAs included CA12, FABP4, DECR1, BAIAP2, IL1RAPL2, PPARD, LAD1, TSPAN10, LDOC1, ZNF853, RP11‐25G10.2, RP11‐557H15.3, RP11‐521D12.5, CHKB‐AS1, RP11‐219B4.3, CH17‐335B8.4, RP11‐99 J16‐A.2, CTB‐111H14.1, ADNP‐AS1, and JHDM1D‐AS1. SFN, IL1RAPL2, and RP11‐25G10.2 were overlapped from grade 1, grade 2, and grade 3. PPI network showed that top 10 proteins with higher degrees, including GNAI1, RAP2B, GNAZ, SHH, ADCY1, PRKAR2B, SH3GL1, GNA15, and ARRB1. A DElncRNAs‐nearby DEmRNAs network was constructed to obtain hub lncRNAs including ADAMTS9‐AS2, RP11‐210 M15.2, RP11‐13 K12.1, ZBED3‐AS1, and RP11‐25G10.2. Except for RP11‐25G10.2, ADAMTS9‐AS1, ZBED3‐AS1, SFN, ATP1A2, and GNA15 were consistent with our TCGA analysis. Conclusions Alterations of DEmRNAs and DElncRNAs may provide key insights into the molecular mechanisms of ESCC.
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Affiliation(s)
- Xin Gao
- Department of Radiotherapy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Oncology, Dongying People's Hospital, Dongying, China
| | - Qian Liu
- Department of Oncology, Dongying People's Hospital, Dongying, China
| | - Xue Chen
- Department of Radiotherapy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shaoping Chen
- Department of Oncology, Dongying People's Hospital, Dongying, China
| | - Jianmei Yang
- Department of Oncology, Dongying People's Hospital, Dongying, China
| | - Qiang Liu
- Department of Oncology, Dongying People's Hospital, Dongying, China
| | - Yufeng Cheng
- Department of Radiotherapy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Fan H, Zaman MAU, Chen W, Ali T, Campbell A, Zhang Q, Setu NI, Saxon E, Zahn NM, Benko AM, Arnold LA, Peng X. Assessment of Phenylboronic Acid Nitrogen Mustards as Potent and Selective Drug Candidates for Triple-Negative Breast Cancer. ACS Pharmacol Transl Sci 2021; 4:687-702. [PMID: 33860194 PMCID: PMC8033613 DOI: 10.1021/acsptsci.0c00092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Indexed: 12/18/2022]
Abstract
Triple-negative breast cancer (TNBC) has limited treatment options and the worst prognosis among all types of breast cancer. We describe two prodrugs, namely, CWB-20145 (1) and its methyl analogue FAN-NM-CH3 (2) that reduced the size of TNBC-derived tumors. The DNA cross-linking of nitrogen mustard prodrugs 1 and 2 was superior to that of chlorambucil and melphalan once activated in the presence of H2O2. The cellular toxicity of 1 and 2 was demonstrated in seven human cancer cell lines. The TNBC cell line MDA-MB-468 was particularly sensitive toward 1 and 2. Compound 2 was 10 times more cytotoxic than chlorambucil and 16 times more active than melphalan. An evaluation of the gene expression demonstrated an upregulation of the tumor suppressor genes p53 and p21 supporting a transcriptional mechanism of a reduced tumor growth. Pharmacokinetic studies with 1 showed a rapid conversion of the prodrug. The introduction of a methyl group generated 2 with an increased half-life. An in vivo toxicity study in mice demonstrated that both prodrugs were less toxic than chlorambucil. Compounds 1 and 2 reduced tumor growth with an inhibition rate of more than 90% in athymic nude mice xenografted with MDA-MB-468 cells. Together, the in vivo investigations demonstrated that treatment with 1 and 2 suppressed tumor growth without affecting normal tissues in mice. These phenylboronic acid nitrogen mustard prodrugs represent promising drug candidates for the treatment of TNBC. However, the mechanisms underlying their superior in vivo activity and selectivity as well as the correlation between H2O2 level and in vivo efficacy are not yet fully understood.
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Affiliation(s)
| | | | | | - Taufeeque Ali
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
| | - Anahit Campbell
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
| | - Qi Zhang
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
| | - Nurul Islam Setu
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
| | - Eron Saxon
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
| | - Nicolas M. Zahn
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
| | - Anna M. Benko
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
| | - Leggy A. Arnold
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
| | - Xiaohua Peng
- Department of Chemistry and
Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, Wisconsin 53211, United States
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9
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Guérin A, Martire D, Trenquier E, Lesluyes T, Sagnol S, Pratlong M, Lefebvre E, Chibon F, de Santa Barbara P, Faure S. LIX1 regulates YAP activity and controls gastrointestinal cancer cell plasticity. J Cell Mol Med 2020; 24:9244-9254. [PMID: 32633461 PMCID: PMC7417687 DOI: 10.1111/jcmm.15569] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/02/2020] [Accepted: 06/12/2020] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumours (GISTs), the most common mesenchymal neoplasm of the gastrointestinal tract, result from deregulated proliferation of transformed KIT‐positive interstitial cells of Cajal that share mesenchymal progenitors with smooth muscle cells. Despite the identification of selective KIT inhibitors, primary resistance and relapse remain a major concern. Moreover, most patients develop resistance partly through reactivation of KIT and its downstream signalling pathways. We previously identified the Limb Expression 1 (LIX1) gene as a unique marker of digestive mesenchyme immaturity. We also demonstrated that LIX1 regulates mesenchymal progenitor proliferation and differentiation by controlling the Hippo effector YAP1, which is constitutively activated in many sarcomas. Therefore, we wanted to determine LIX1 role in GIST development. We found that LIX1 is strongly up‐regulated in GIST samples and this is associated with unfavourable prognosis. Moreover, LIX1 controls GIST cell proliferation in vitro and in vivo. Upon LIX1 inactivation in GIST cells, YAP1/TAZ activity is reduced, KIT (the GIST signature) is down‐regulated, and cells acquire smooth muscle lineage features. Our data highlight LIX1 role in digestive mesenchyme‐derived cell‐fate decisions and identify this novel regulator as a target for drug design for GIST treatment by influencing its differentiation status.
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Affiliation(s)
- Amandine Guérin
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Delphine Martire
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Eva Trenquier
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Tom Lesluyes
- Cancer Research Center of Toulouse, University of Toulouse, INSERM, CNRS, Toulouse, France
| | - Sébastien Sagnol
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Marine Pratlong
- MGX, Biocampus Montpellier, CNRS, INSERM, University of Montpellier, Montpellier, France
| | - Elise Lefebvre
- MGX, Biocampus Montpellier, CNRS, INSERM, University of Montpellier, Montpellier, France
| | - Fréderic Chibon
- Cancer Research Center of Toulouse, University of Toulouse, INSERM, CNRS, Toulouse, France
| | | | - Sandrine Faure
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
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10
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Haplotype-Based Genome-Wide Association Study and Identification of Candidate Genes Associated with Carcass Traits in Hanwoo Cattle. Genes (Basel) 2020; 11:genes11050551. [PMID: 32423003 PMCID: PMC7290854 DOI: 10.3390/genes11050551] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 12/20/2022] Open
Abstract
Hanwoo, is the most popular native beef cattle in South Korea. Due to its extensive popularity, research is ongoing to enhance its carcass quality and marbling traits. In this study we conducted a haplotype-based genome-wide association study (GWAS) by constructing haplotype blocks by three methods: number of single nucleotide polymorphisms (SNPs) in a haplotype block (nsnp), length of genomic region in kb (Len) and linkage disequilibrium (LD). Significant haplotype blocks and genes associated with them were identified for carcass traits such as BFT (back fat thickness), EMA (eye Muscle area), CWT (carcass weight) and MS (marbling score). Gene-set enrichment analysis and functional annotation of genes in the significantly-associated loci revealed candidate genes, including PLCB1 and PLCB4 present on BTA13, coding for phospholipases, which might be important candidates for increasing fat deposition due to their role in lipid metabolism and adipogenesis. CEL (carboxyl ester lipase), a bile-salt activated lipase, responsible for lipid catabolic process was also identified within the significantly-associated haplotype block on BTA11. The results were validated in a different Hanwoo population. The genes and pathways identified in this study may serve as good candidates for improving carcass traits in Hanwoo cattle.
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PLCB4 upregulation is associated with unfavorable prognosis in pediatric acute myeloid leukemia. Oncol Lett 2019; 18:6057-6065. [PMID: 31788080 PMCID: PMC6865073 DOI: 10.3892/ol.2019.10921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 08/21/2019] [Indexed: 02/07/2023] Open
Abstract
Phospholipase C (PLC) is a membrane-associated enzyme that regulates several cellular behaviors including cell motility, growth, transformation and differentiation. PLC is involved in cancer migration, invasion and drug resistance. However, the expression status and prognostic role of PLCB4 in acute myeloid leukemia (AML) remain unclear. In the present study, the complete clinical and mRNA expression data of 285 pediatric patients with de novo AML were obtained from the Therapeutically Available Research to Generate Effective Treatments database. The association between PLCB4 expression and clinical and molecular features was explored. The expression of PLCB4 was significantly higher in patients with AML who relapsed compared with those with long-term complete remission. Patients with PLCB4 upregulation had significantly lower overall survival (OS) and event free survival (EFS) rate compared with those with low PLCB4 expression. Multivariate Cox's regression analyses demonstrated that high PLCB4 expression was an independent risk factor of adverse OS (P<0.01; HR, 2.081) and EFS (P<0.01; HR, 2.130). Following stratification analysis according to transplant status in cases of first complete remission, the patients with high expression of PLCB4 had significantly lower OS and EFS rate in the chemotherapy group, but not the stem cell transplant group. Furthermore, PLCB4-associated genes were identified using Spearman's rank correlation analysis. KEGG pathway analysis revealed that PLCB4 and its associated genes were mainly involved in three potential pathways, including the Rap1 signaling pathway. Overall, the findings of the present study suggest that increased PLCB4 expression is associated with poor clinical outcome in pediatric patients with AML, and thus may represent a potential prognostic biomarker and therapeutic target for AML.
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12
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Chen T, Ye LY, Feng XY, Qiu HB, Zhang P, Luo YX, Yuan LY, Chen XH, Hu YF, Liu H, Li Y, Tao KX, Yu J, Li GX. Performance of risk stratification systems for gastrointestinal stromal tumors: A multicenter study. World J Gastroenterol 2019; 25:1238-1247. [PMID: 30886506 PMCID: PMC6421238 DOI: 10.3748/wjg.v25.i10.1238] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/30/2019] [Accepted: 02/15/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor type in the gastrointestinal system. Presently, various classification systems to prognosticate GISTs have been proposed. AIM To evaluate the application value of four different risk stratification systems for GISTs. METHODS Patients who were diagnosed with GISTs and underwent surgical resection at four hospitals from 1998 to 2015 were identified from a database. Risk of recurrence was stratified by the modified National Institute of Health (NIH) criteria, the Armed Forces Institute of Pathology (AFIP) criteria, the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic nomogram, and the contour maps. Receiver operating characteristic (ROC) curves were established to compare the four abovementioned risk stratification systems based on the area under the curve (AUC). RESULTS A total of 1303 patients were included in the study. The mean age of the patients was 55.77 ± 13.70 yr; 52.3% of the patients were male. The mean follow-up period was 64.91 ± 35.79 mo. Approximately 67.0% the tumors were located in the stomach, and 59.5% were smaller than 5 cm; 67.3% of the patients had a mitotic count ≤ 5/50 high-power fields (HPFs). Thirty-four tumors ruptured before and during surgery. Univariate analysis demonstrated that tumor size > 5 cm (P < 0.05), mitotic count > 5/50 HPFs (P < 0.05), non-gastric location (P < 0.05), and tumor rupture (P < 0.05) were significantly associated with increased recurrence rates. According to the ROC curve, the AFIP criteria showed the largest AUC (0.754). CONCLUSION According to our data, the AFIP criteria were associated with a larger AUC than the NIH modified criteria, the MSKCC nomogram, and the contour maps, which might indicate that the AFIP criteria have better accuracy to support therapeutic decision-making for patients with GISTs.
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Affiliation(s)
- Tao Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Liang-Ying Ye
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xing-Yu Feng
- Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Hai-Bo Qiu
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou 510060, Guangdong Province, China
| | - Peng Zhang
- Department of General Surgery, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yi-Xin Luo
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Li-Yi Yuan
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xin-Hua Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yan-Feng Hu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Yong Li
- Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Kai-Xiong Tao
- Department of General Surgery, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Guo-Xin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Haider Z, Larsson P, Landfors M, Köhn L, Schmiegelow K, Flaegstad T, Kanerva J, Heyman M, Hultdin M, Degerman S. An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression. Cancer Med 2018; 8:311-324. [PMID: 30575306 PMCID: PMC6346238 DOI: 10.1002/cam4.1917] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/12/2018] [Accepted: 11/19/2018] [Indexed: 01/01/2023] Open
Abstract
Classification of pediatric T‐cell acute lymphoblastic leukemia (T‐ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T‐ALL patients were characterized by genome‐wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2‐1, and novel genes in T‐ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP− subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL‐TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP−), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T‐ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies.
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Affiliation(s)
- Zahra Haider
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Pär Larsson
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Mattias Landfors
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Linda Köhn
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Kjeld Schmiegelow
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
| | - Trond Flaegstad
- Department of Pediatrics, University of Tromsø and University Hospital of North Norway, Tromsø, Norway
| | - Jukka Kanerva
- Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - Mats Heyman
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Hultdin
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
| | - Sofie Degerman
- Department of Medical Biosciences, Umeå University, Umeå, Sweden
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Li CF, Liu TT, Wang JC, Yu SC, Chen YY, Fang FM, Li WS, Huang HY. Hydroxysteroid 11-Beta Dehydrogenase 1 Overexpression with Copy-Number Gain and Missense Mutations in Primary Gastrointestinal Stromal Tumors. J Clin Med 2018; 7:408. [PMID: 30388854 PMCID: PMC6262574 DOI: 10.3390/jcm7110408] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 10/25/2018] [Accepted: 10/29/2018] [Indexed: 12/11/2022] Open
Abstract
The lipid-metabolizing enzymes remain underexplored in gastrointestinal stromal tumors (GISTs). Through transcriptomic reappraisal, hydroxysteroid 11-beta dehydrogenase-1 (HSD11B1) was identified as a top-upregulated, progression-associated gene. To validate the clinical relevance of HSD11B1, the informative results of Sanger sequencing (n = 58), mRNA quantification by branched-chain DNA in situ hybridization assay (n = 70), copy number assay by fluorescent in situ hybridization (n = 350), and immunohistochemistry (n = 350) were correlated with clincopathological variables, KIT/PDGFRA/BRAF genotypes, and disease-free survival (DFS). HSD11B1 was stably silenced to explore its oncogenic function. HSD11B1 mRNA varied between high-risk and non-high-risk groups (p = 0.009) and positively correlated with HSD11B1 immunoexpression (r = 0.783, p < 0.001). HSD11B1 copy-number gain (CNG), including polysomy (5.4%) and amplification (12%), associated with HSD11B1 overexpression (p < 0.001). Predominantly involving the homodimer interface-affecting exon 6 or exon 7, missense HSD11B1 mutations (17.2%) were related to high risk (p = 0.044), age ≥70 years (p = 0.007), and shorter DFS among relapsed cases (p = 0.033). CNG was related to unfavorable KIT/PDGFRA/BRAF genotypes (p = 0.015), while HSD11B1 overexpression was preferential in non-gastric cases (p < 0.001). Both abnormalities strongly associated with risk levels (both p < 0.001) and shorter univariate DFS (both p < 0.0001), and HSD11B1 CNG remained prognostically independent (p < 0.001) with a 3-fold increased hazard ratio. In vitro, HSD11B1 knockdown significantly inhibited proliferation and caused G2/M arrest. In conclusion, HSD11B1 overexpression may occur owing to CNG, confer a pro-proliferative function, and predict a worse prognosis in GISTs.
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Affiliation(s)
- Chien-Feng Li
- Department of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan.
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan.
- Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Kaohsiung 833, Taiwan.
| | - Ting-Ting Liu
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Jui-Chu Wang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Shih-Chen Yu
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Yen-Yang Chen
- Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Fu-Min Fang
- Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Wan-Shan Li
- Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Kaohsiung 833, Taiwan.
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
| | - Hsuan-Ying Huang
- Bone and Soft Tissue Study Group, Taiwan Society of Pathology, Kaohsiung 833, Taiwan.
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
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Condorelli DF, Spampinato G, Valenti G, Musso N, Castorina S, Barresi V. Positive Caricature Transcriptomic Effects Associated with Broad Genomic Aberrations in Colorectal Cancer. Sci Rep 2018; 8:14826. [PMID: 30287863 PMCID: PMC6172234 DOI: 10.1038/s41598-018-32884-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 09/07/2018] [Indexed: 12/12/2022] Open
Abstract
We re-examined the correlation between Broad Genomic Aberrations (BGAs) and transcriptomic profiles in Colorectal Cancer (CRC). Two types of BGAs have been examined: Broad Copy-Number Abnormal regions (BCNAs), distinguished in gain- and loss-type, and Copy-Neutral Loss of Heterozygosities (CNLOHs). Transcripts are classified as “OverT” or “UnderT” if overexpressed or underexpressed comparing CRCs bearing a specific BGA to CRCs not bearing it and as “UpT” or “DownT” if upregulated or downregulated in cancer compared to normal tissue. BGA-associated effects were evaluated by changes in the “Chromosomal Distribution Index” (CDI) of different transcript classes. Data show that UpT are more sensitive than DownT to BCNA-associated gene dosage effects. “Over-UpT” genes are upregulated in cancer and further overexpressed by gene dosage, defining the so called “positive caricature transcriptomic effect”. When Over-UpT genes are ranked according to overexpression, top positions are occupied by genes implicated at the functional and therapeutic level in CRC. We show that cancer-upregulated transcripts are sensitive markers of BCNA-induced effects and suggest that analysis of positive caricature transcriptomic effects can provide clues toward the identification of BCNA-associated cancer driver genes.
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Affiliation(s)
- Daniele F Condorelli
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Catania, (95123), Italy.
| | - Giorgia Spampinato
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Catania, (95123), Italy
| | - Giovanna Valenti
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Catania, (95123), Italy
| | - Nicolò Musso
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Catania, (95123), Italy
| | - Sergio Castorina
- Department of Medical and Surgical Sciences and Advanced Technologies, University of Catania, Catania, (95123), Italy
| | - Vincenza Barresi
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Catania, (95123), Italy.
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Namous H, Peñagaricano F, Del Corvo M, Capra E, Thomas DL, Stella A, Williams JL, Marsan PA, Khatib H. Integrative analysis of methylomic and transcriptomic data in fetal sheep muscle tissues in response to maternal diet during pregnancy. BMC Genomics 2018; 19:123. [PMID: 29409445 PMCID: PMC5801776 DOI: 10.1186/s12864-018-4509-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 01/29/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Numerous studies have established a link between maternal diet and the physiological and metabolic phenotypes of their offspring. In previous studies in sheep, we demonstrated that different maternal diets altered the transcriptome of fetal tissues. However, the mechanisms underlying transcriptomic changes are poorly understood. DNA methylation is an epigenetic mark regulating transcription and is largely influenced by dietary components of the one-carbon cycle that generate the methyl group donor, SAM. Therefore, in the present study, we tested whether different maternal diets during pregnancy would alter the DNA methylation and gene expression patterns in fetal tissues. RESULTS Pregnant ewes were randomly divided into two groups which received either hay or corn diet from mid-gestation (day 67 ± 5) until day 131 ± 1 when fetuses were collected by necropsy. A total of 1516 fetal longissimus dorsi (LD) tissues were used for DNA methylation analysis and gene expression profiling. Whole genome DNA methylation using methyl-binding domain enrichment analysis revealed 60 differentially methylated regions (DMRs) between hay and corn fetuses with 39 DMRs more highly methylated in the hay fetuses vs. 21 DMRs more highly methylated in the corn fetuses. Three DMRs (LPAR3, PLIN5-PLIN4, and the differential methylation of a novel lincRNA) were validated using bisulfite sequencing. These DMRs were associated with differential gene expression. Additionally, significant DNA methylation differences were found at the single CpG level. Integrative methylome and transcriptome analysis revealed an association between gene expression and inter-/intragenic methylated regions. Furthermore, intragenic DMRs were found to be associated with expression of neighboring genes. CONCLUSIONS The findings of this study imply that maternal diet from mid- to late-gestation can shape the epigenome and the transcriptome of fetal tissues, and putatively affect phenotypes of the lambs.
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Affiliation(s)
- Hadjer Namous
- Department of Animal Sciences, University of Wisconsin, 1675 Observatory Drive, Madison, WI 53706 USA
| | - Francisco Peñagaricano
- Department of Animal Sciences, University of Florida Genetics Institute, University of Florida, Florida, USA
| | - Marcello Del Corvo
- Institute of Zootechnics and PRONUTRIGEN Research Center, Faculty of Agricultural, Food and Environmental Sciences, Università Cattolica del S. Cuore, Piacenza, Italy
| | - Emanuele Capra
- Istituto di Biologia e Biotecnologia Agraria, Consiglio Nazionale delle Ricerche, Lodi, Italy
| | - David L. Thomas
- Department of Animal Sciences, University of Wisconsin, 1675 Observatory Drive, Madison, WI 53706 USA
| | - Alessandra Stella
- Istituto di Biologia e Biotecnologia Agraria, Consiglio Nazionale delle Ricerche, Lodi, Italy
| | - John L. Williams
- Davies Research Centre, School of Animal and Veterinary Sciences, University of Adelaide, Roseworthy, Australia
| | - Paolo Ajmone Marsan
- Institute of Zootechnics and PRONUTRIGEN Research Center, Faculty of Agricultural, Food and Environmental Sciences, Università Cattolica del S. Cuore, Piacenza, Italy
| | - Hasan Khatib
- Department of Animal Sciences, University of Wisconsin, 1675 Observatory Drive, Madison, WI 53706 USA
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17
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Li CF, Fang FM, Chen YY, Liu TT, Chan TC, Yu SC, Chen LT, Huang HY. Overexpressed Fatty Acid Synthase in Gastrointestinal Stromal Tumors: Targeting a Progression-Associated Metabolic Driver Enhances the Antitumor Effect of Imatinib. Clin Cancer Res 2017; 23:4908-4918. [PMID: 28442505 DOI: 10.1158/1078-0432.ccr-16-2770] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 03/02/2017] [Accepted: 04/19/2017] [Indexed: 11/16/2022]
Abstract
Purpose: In gastrointestinal stromal tumors (GIST), lipid-metabolizing enzymes remain underexplored, including fatty acid synthase (FASN).Experimental Design: Forty GISTs were quantitated for FASN mRNA abundance. FASN immunoexpression was informative in 350 GISTs, including 213 with known KIT/PDGFRA/BRAF genotypes. In imatinib-resistant FASN-overexpressing GIST cells, the roles of overexpressed FASN and FASN-targeting C75 in tumor phenotypes, apoptosis and autophagy, KIT transcription, PI3K/AKT/mTOR activation, and imatinib resistance were analyzed by RNAi or myristoylated-AKT transfection. The therapeutic relevance of dual blockade of FASN and KIT was evaluated in vivoResults:FASN mRNA abundance significantly increased from very low/low-risk to high-risk levels of NCCN guidelines (P < 0.0001). FASN overexpression was associated with a nongastric location (P = 0.05), unfavorable genotype (P = 0.005), and increased risk level (P < 0.001) and independently predicted shorter disease-free survival (P < 0.001). In vitro, FASN knockdown inhibited cell growth and migration, inactivated the PI3K/AKT/mTOR pathway, and resensitized resistant GIST cells to imatinib. C75 transcriptionally repressed the KIT promoter, downregulated KIT expression and phosphorylation, induced LC3-II and myristoylated AKT-suppressible activity of caspases 3 and 7, attenuated the PI3K/AKT/mTOR/RPS6/4E-BP1 pathway activation, and exhibited dose-dependent therapeutic additivism with imatinib. Compared with both monotherapies, the C75/imatinib combination more effectively suppressed the growth of xenografts, exhibiting decreased KIT phosphorylation, Ki-67, and phosphorylated PI3K/AKT/mTOR levels and increased TUNEL labeling.Conclusions: We have characterized the prognostic, biological, and therapeutic implications of overexpressed FASN in GISTs. C75 represses KIT transactivation, abrogates PI3K/AKT/mTOR activation, and provides a rationale for dual blockade of KIT and FASN in treating imatinib-resistant GISTs. Clin Cancer Res; 23(16); 4908-18. ©2017 AACR.
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Affiliation(s)
- Chien-Feng Li
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Fu-Min Fang
- Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yen-Yang Chen
- Division of Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ting-Ting Liu
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Ti-Chun Chan
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
| | - Shih-Chen Yu
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Hsuan-Ying Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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